Activating Multiorgan Antioxidative Gene Network for Treating Sepsis ABSTRACT Despite more than three decades of extensive research, sepsis remains the chief cause of death in intensive care units. Currently, there is no specific treatment for sepsis. Thus, it is imperative to develop effective therapies for managing this dread disorder. The exact pathophysiology of sepsis remains to be elucidated. It is thought that sepsis is the culmination of complex interactions between the infecting microorganisms and the host inflammatory cells, leading to dysregulated inflammation, multiple organ failure, and death. In this context, substantial studies support a causal role for reactive oxygen and nitrogen species (ROS/RNS) and the consequent oxidative/inflammatory stress in the development and progression of multiple organ injury in sepsis in both animals and humans. However, exogenous antioxidant-based therapies have been unsuccessful possibly due to their limited ability to scavenge ROS/RNS and counteract oxidative/inflammatory stress. As coordinated actions of a series of endogenous Nrf2-regulated antioxidative/anti-inflammatory (AO/AI) enzymes are essential for efficient detoxification of ROS/RNS in target organs, we propose a novel strategy to treat sepsis via activating the endogenous Nrf2-regulated AO/AI gene network in multiple vital organs. Our long- term objective is to develop an innovative mechanistically-based effective modality targeting multiple vital organs to treat sepsis. The central hypothesis of this R15 application is that the simultaneous coordinated activation of the Nrf2-regulated AO/AI gene network in multiple organs by the novel Nrf2-activating agent, 3H- 1,2-dithiole-3-thione (D3T) is an innovative and highly effective therapeutic strategy to protect against oxidative/inflammatory stress and multiorgan dysfunction and failure in experimental sepsis. This hypothesis is supported by our preliminary studies showing a nearly complete protection by D3T against endotoxemia- induced mortality in mice. Accordingly, the specific aims of this R15 proposal are designed to systematically (1) investigate the upregulation of endogenous AO/AI defenses by D3T in multiple organs, including the heart, lung, liver, kidney, and intestine, and the underlying signaling mechanisms in mice; (2) determine the therapeutic effects of D3T-induced multiorgan AO/AI defenses in the pathophysiological process of LPS- induced endotoxemia and the signaling mechanisms in mice; and (3) investigate the therapeutic effects of D3T-induced multiorgan AO/AI defenses in the pathophysiological process of polymicrobial sepsis induced by cecal ligation and puncture (CLP) and the signaling mechanisms in mice. The proposed studies will provide novel insights into the molecular basis of pharmacological activation of multiorgan AO/AI genes to protect against multiple organ dysfunction and failure in sepsis and will contribute to the development of an effective D3T-based therapeutic modality targeting Nrf2-regulated multiorgan AO/AI genes to treat human sepsis. This project is well within the PI?s extensive research and student training expertises, and will provide a unique opportunity for training additional undergraduate students doing innovative research at the PI?s institution.